Dataset Information

Characterization of a new mouse p53 variant: loss-of-function and gain-of-function.

ABSTRACT: BACKGROUND: p53 is a major tumor suppressor that is inactivated in over 50% of human cancer types through either mutation or inactivating interactions with viral or cellular proteins. The uncertainties around the link between p53 status, therapeutic response, and outcome in cancer suggest that additional factors may be involved. p53 isoforms that are generated via the alternative splicing pathway may be promising candidates for further investigation. RESULT: In this study, we report one new p53 protein with two internally deleted regions, resulting in one deleted amino acid fragment (from amino acid residues 42 to 89) and one reading frame-shift region (from amino acid residues 90-120) compared to wild-type p53. The functional status of the new p53 protein, which has a defect in its proline-rich and N-terminal DNA-binding domains, was characterized as possessing an intact conformation, exhibiting no transactivation activity, exerting a dominant-negative effect and an interacting with a coactivator with an arginine methyltransferase activity. CONCLUSION: Taken together, our findings provide valuable information about the structure and function of p53 for the regulation of transactivation activity and cellular protein-protein interactions. Furthermore, natural p53 isoforms will help us understand the functional roles of the p53 family and potential therapeutics for p53-dependent cancers.

SUBMITTER: Chan JY

PROVIDER: S-EPMC4022406 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Characterization of a new mouse p53 variant: loss-of-function and gain-of-function.

Chan James Yi-Hsin JY Chen Ying-Chuan YC Liu Shu-Ting ST Chou Wei-Yuan WY Ho Ching-Liang CL Huang Shih-Ming SM

Journal of biomedical science 20140508

<h4>Background</h4>p53 is a major tumor suppressor that is inactivated in over 50% of human cancer types through either mutation or inactivating interactions with viral or cellular proteins. The uncertainties around the link between p53 status, therapeutic response, and outcome in cancer suggest that additional factors may be involved. p53 isoforms that are generated via the alternative splicing pathway may be promising candidates for further investigation.<h4>Result</h4>In this study, we report ...[more]

PMID: 24884657

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Project description:Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the ITGB3 gene encoding the integrin ?3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The ITGB3 coding polymorphism Leu33Pro (rs5918, PlA2) produces hyperactive ?v?3 receptors that influence whole-blood 5-HT levels and may influence the risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an Itgb3 variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced ?v?3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT function in synapses of KI mice, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin ?v?3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin ?v?3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders.SIGNIFICANCE STATEMENT The integrin ?3 Leu33Pro coding polymorphism has been associated with autism spectrum disorders (ASDs) within a subgroup of patients with elevated blood 5-HT levels, linking integrin ?3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine integrin ?3 recapitulates the sex-dependent neurochemical and behavioral attributes of ASD. Using state-of-the-art techniques, we show that presynaptic 5-HT function is altered in these mice, and that the localization of 5-HT transporters to specific compartments within the synapse, disrupted by the integrin ?3 Pro33 mutation, is critical for appropriate reuptake of 5-HT. Our studies provide fundamental insight into the genetic network regulating 5-HT neurotransmission in the CNS that is also associated with ASD risk.

Dataset Information

Characterization of a new mouse p53 variant: loss-of-function and gain-of-function.

Publications

Characterization of a new mouse p53 variant: loss-of-function and gain-of-function.

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